Highly cultured New
Sci 19 aug 2000
Cells with an identity crisis can mature into life-saving brain
or liver tissue... possibly anything we like

Put it to the Vote New Sci 19 aug 2000

REVOLUTIONARY medical treatments that replace damaged organs
with replicas made from a patient's own tissue or from "off-the-shelf"
tissue banks moved a stage closer this week in Britain.
In a momentous decision that could catalyse similar moves in other
industrialised countries, Tony Blair's goverrunent has recommended
changes to the law that would allow controversial research on
human embryos. But the British government is not ordering its
own MPs to vote for the changes in the law. When the proposed
legislation is presented to MPs later this year, they will be
free to vote according to their consciences. To make the spare
organs, doctors would use so-called stem cells, primordial cells
that can grow into almost any type of tissue. These stem cells
could hopefully be grown into the tissue of choice, such as muscle,
heart, liver or lung. "Off-the-shelf" tissue could be
created from mass-produced stem cells stored in tissue banks.
Patients would either receive immunosuppressive drugs to stop
them rejecting the graft, or cells might be tissuetyped to suit
groups of patients in the way that blood groups are now. An altemative
is "therapeutic cloning", a way of making perfectly
matched organs from a patient's own tissue by applying the technique
used to create Dolly the sheep. Doctors would take a patient's
cell, from skin say, then fuse it with a donated human egg stripped
of its own genetic material. The cells would divide to create
an early embryo, or blastocyst, from which stem cans could be
harvested (see Diagram). The problem is that in both these cases,
the stem cells come from embryos. Pro-life groups oppose such
research because they believe it means killing a potential human
being, even though the cells in blastocysts have not changed into
specialised tissues and organs. At present in Britain, researchers
can legally experiment on embryos up to 14 days old, but only
in five research categories linked to infertility. In December
1998, a panel of advisers urged the government to change the law
to allow two further categories.

One was therapeutic cloning; the other would allow research
using the Dolly technique to treat inherited diseases of mitochondria,
the energy factories of cells. The recommendations came from a
joint report by the government's independent Human Genetics Advisory
Commission (HGAC) and the Human Fertilisation and Embryology Authority
(HFEA). But the government responded in May 1999 by stalling,
setting up a second panel to re-examine the issue under its Chief
Medical Officer, Liam Donaldson. This week, the government finally
released the Donaldson report. Blair's govenunent is now backing
in full the changes that would legalise the two new categories
of embryo research. But Mps will be allowed to vote on the issue.
Some have attacked the free vote as a ploy to avoid offending
opponents of therapeutic cloning, such as the Catholic Church.
"It shows lack of leadership," says Alistair Kent of
the Genetic Interest Group, which represents patients with hereditary
diseases. "To put it to a free vote is to abdicate responsibility
for taking control." Others are more conciliatory. "It's
right to say that a moral issue of this sort is put to a free
vote," says Martin Bobrow, a medical geneticist at the University
of Cambridge and a member of the HGAC, which originally proposed
the law change. There is also pressure for change in the US, where
government researchers are banned from working on stem cells to
avoid offending the pro-life lobby. The ban does not apply in
the private sector, however, and calls are intensifying for govemment
labs to be allowed to do the research to avoid monopolisation
for private gain. Within weeks, the National Institutes of Health
is expected to issue guidelines allowing federal researchers to
work on but not harvest stem cells from embryos. A bill passing
through Congress goes further, proposing that federal money should
lYe used both to harvest and work on stem cells. Ironically, the
bill has found support among many Republicans who are pro-lifers.
Despite their stance on abortion they reject the notion that embryos
left over from IVF treatment are potential human beings. They
have been persuaded by personal experience with illnesses and
by patients' rights groups who say that it's morally reprehensible
to deny them new treatments. Other groups, such as the United
Methodist Church, oppose it on the grounds that it brings human
life closer to being a commodity. A stronger argument, perhaps,
is that adult stem cells might prove to be a way round the whole
problem because they don't come from embryos (see p 16). "Why
should we start opening up this entire ethical quagmire when we
really don't need to," says Gene Tarne of the Coalition of
Americans for Research Ethics. Researchers agree with this, but
argue it can't happen without research on embryos first (see p
15). Tom Okarma, chief execufive of Geron in Califomia, which
has exclusive access to stem cells (see p 14), says research would
accelerate if the federal research ban was lifted: "It's
a medical and global tragedy that this is taking so long."
Andy Coghlan and Nell Boyce, Washington, DC

Highly cultured New Sci 19 aug 2000
Cells with an identity crisis can mature into life-saving brain
or liver tissue... possibly anything we like

TAMPERING with stem cells from human embryos might be a political
hot potato, but the benefits could be huge. Already, scientists
have coaxed human stem cells to tum into brain, liver, muscle
and beating heart cells. And results from animal experiments hint
that the cultured cells should function as normal when transplanted.
This could lead to new treatments for a host of diseases, such
as Parkinson's. Earlier this year, a team led by Alan Trounson
and Michael Pera at Monash University in Melbourne announced they
had grown primitive muscle and nerve cells from human embryonic
stem cells (New Scientist, 8 April, p 4). They sidestepped an
Australian ban on using human embryonic stem cells by working
in Singapore And the private company Geron of Menlo Park, California,
says it is even further ahead, thanks to commercial deals that
give it exclusive access to the only current sources of stem cells
in the US. In research yet to be published, Geron researchers
have turned unspecialised "pluripotent" stem cells into
the three major types of nerve cell: neurons, which conduct electrical
signals; astrocytes, which nourish and insulate neurons; and oligodendrocytes,
which form a sheath around nerve cells. Geron researchers have
also turned pluripotent stem cells into liver cells. "We've
derived what look like liver cells, although we need more work
to be sure," says Tom Okarma, the company's chief executive.
Geron has also created heart cells called cardiomyocytes that
beat in the test tube. The company plans to do animal tests on
all the cell types to see if they function. In earlier experiments
on transformed stem cells from mice, Geron scientists found that
pancreatic islet cells-which synthesise insulin-cardiomyocytes
and neural cells all functioned perfectly. The mouse experiments
suggest that the key to successful transplants is to inject cells
that are on the verge of becoming the desired tissue. Geron has
not yet announced which substances it uses to make the cells differentiate.
"They include some reagents that have been used before, and
some innovations we've developed ourselves," says OkarmaThe
company is now trying to pin down exactly how this process works
at the genetic level during natural development. While Geron tries
to find out how stem cells differentiate, its collaborators at
Geron BioMed-a company created with the Roslin Institute in Edinburgh,
which cloned Dolly the sheep-are doing the opposite. They are
trying to find out how the identity of differentiated cells can
be wiped out so that they behave as stem cells again. Roslin researchers
are working on sheep, mouse and pig eggs to try to find clues
to the mechanisms operating in human eggs. Scientists have also
made steps towards "therapeutic cloning"-using cloning
techniques to extract stem cells and grow spare body parts without
the risk of rejection. A patient's tissue would be cloned by fusing
one of his or her own cells with a human egg stripped of its own
genetic material. In a paper in this week's o@e Current Biology,
Pera, Trounson and their colleague Megan Munsie say they have
extracted stem cells from mice this way. "It's proof of principle,"
says Pera. "We're pretty excited about it." But anti-abortion
protesters have condemned using human eggs in this way The Roslin
team is trying to get round it by "reprogramming" a
patient's cell using a cluster of stem cells cultured from a human
cell line rather than an egg. Experiments in 1997 by Azim Surani
of the Institute of Cancer Research in Cambridge suggested that
an adult mouse cell could be reprogrammed by fusing it with a
clump of embryonic mouse stem cells stripped of their nuclear
DNA (New Scientist, 29 January, p 4). So a clump of cultured cells
could serve as a standardised "capsule" for reprogramming
a patient's own cells. But before any of this can happen, validation
experiments will have to take place using human eggs. "We'd
have to do the tests to be sure that the factors we think are
relevant in animal cells do the same thirig iri human cells,"
says Okarma. Andy Coghlan

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The right to study human embryos could solve one of the most
serious ethical dilemmas of stem cell research

BRITAIN'S only researcher licensed to experiment on human stem
cells from embryos is keen to get the green light for tissue research
following the publication of the Donaldson report (p 4). Austin
Smith, director of the Centre for Genome Research at the University
of Edinburgh, stresses that only through research on stem cells
from human embryos can we learn how to refashion tissue without
creating embryos in the process. Smith is licensed to experiment
on human stem cells in Britain because his objective is to improve
infertility treatmentone of five categories of research for which
human embryos up to 14 days old can legally be used. He finds
it frustrating that the cells he extracts for infertility experiments
can't be used to develop tissues for transplant. Smith worries
that the current limits on goverrunent-funded embryo research
in Britain and the US push the research into the American private
sector, which is not govemed by regulations. "I want to know
I'm going forward with public support and public confidence, and
that everything I do will be transparent and published, and not
part of some commercial enterprise," he says. "It's
vitally important to have a public effort too." One way to
bypass the ban would be to import ready-isolated human stem cells
from abroad for experimentation. But Smith says even this might
not work: "You don't know what the cells might have been
treated with or their history." He hopes it might soon be
possible to grow tissue without creating a short-lived human embryo
in the process. The holy grail of stem cell research would be
to pluck cells directly from a patient, "reprogram"
them with chemicals and convert them straight into tissue for
transplant.

But the chemical recipes for this direct cell reprogramming
can only be learned through experiments on stem cells from human
embryos, Smith says. Animal cells can never reveal how to reprogram
human cells because they use different chemical signals. C)nly
by isolating the substances from empty human eggs that rewind
adult cells back to zero-which is what happened when Dolly the
sheep was cloned@an we leam how to do the same thing by chemical
manipulation, he says. Andy Coghlan

Old cells, new tricks New Sci
19 aug 2000 The furore over embryonic cells could be side-stepped

ADULT stem cells may be able to perform many of the same tricks
as embryonic stem cells. If so, the ethical debates about the
use of human embryos could be avoided. Adult mammals have about
20 types of stem cell. It was thought these cells gave rise to
only specific cell lines-for example, that blood stem cells could
only turn into blood cells-but scientists are now discovering
how versatile these cells are. Angelo Vescovi of Italy's National
Neurological Institute in Milan showed in 1999 that mouse brain
stem cells could produce blood cells when injected into mice whose
bone marrow-the normal bloodmaking tissue-had been largely destroyed.
Since Vescovi made this discovery, many similar observations have
been made. "The concept that these cells could differentiate
into different tissues was very surprising," says Margaret
Goodell of Baylor College of Medicine in Texas, who recently discovered
that cells from muscles could repopulate the blood system of mice.
But just how versatile are adult cells? "Although the cells
show potential, it's premature to say they can totally substitute
embryonic stem cells," Goodell cautions. jonas Fris6n's work
at the Karolinska Institute in Stockholm, however, suggests that
brain stem cells can perform many of the same feats as embryonic
stem cells. His group injected early embryos with the adult stem
cells and found descendants of these cells in various organs,
including the heart, liver, intestine and nervous system.

But was a rare kind of brain stem cell responsible, or is there
something in the embryo that can reprogram an adult stem cell?
No one knows, but researchers are hoping it's a rare cell that
can be cultured. Taking brain stem cells from people, though,
is not very practical. Fortunately, other adult stem cells seem
just as versatile. Malcolm Alison of the Imperial College School
of Medicine recently showed that liver cells can be derived from
blood stem cells, for example. Such cells could be taken from
patients themselves, but they are scarce, and Alison has yet to
discover how to isolate them. A method developed by David Scadden
at Massachusetts General Hospital, however, could help Alison
and others. Scadden uses electrical pulses to kill large cells,
leaving behind more of the smaller stem cells. Even when they
can be isolated, adult stem cells lose their ability to divide
after a time, whereas embryonic stem cells divide indefinitely.
"Finding a way to turn blood stem cells into liver cells,
or into other cell types, and keep them dividing in a culture
dish, is the huge challenge of the future," says Alison.
Diane Martindale

Making more of yourself

THIRTY years from now, scientists will be growing whole hearts,
livers and even limbs in high-tech labs. "We just need a
reliable source of cells," says Anthony Atala, a urologist
at the Children's Hospital in Boston. His team has grown artificial
bladders for beagles using tissue taken from normal dog bladders.
The harvested tissue was cultured until there was enough to "seed"
a biodegradable "scaffold"-a growth surface in the shape
of the organ. Transplanted into dogs, the new organs served their
recipients well for the 1 1 months of the experiment. Atala's
organs did not use stem cells. But in future, embryonic stem cells
might be used to begin making a complex organ in the lab before
the r, organ is transplanted into the body to finish growing.
The dog bladders took six weeks to grow. A more complex organ,
such as a kidney, might take several months. This approach is
promising, says tissue engineer Robert Langer at the Massachusetts
Institute of Technology in Boston, because the body can overcome
two of the biggest difficulties faced in the lab-providing an
adequate supply of oxygen and nutrients and a three-dimensional
"frame" to give cells the proper cues for growing into
the right shape. Clever tissue reconstruction techniques already
make replacement ears and noses. But the manipulation of stem
cells will allow more complex organs to be made. No more organ
donor short ages, no more tissue rejection: medicine will be revolutionised.
Diane Martindale

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Trapped among your own genes are those of ancient viral invaders
that plagued our ancestors. Could these fossil viruses be to blame
when our immune system turns traitor? Bryant Furlow investigates

IT'S DARK. As you drift off to sleep, a noise outside yanks
you back into the wakeful world. Instantly alert, your heart pounds
against your ribs. A moment later you hear a snarling bark and
a crash as the intruders beat a hasty retreat. Panic over-good
old Fido has seen them off. But imagine that instead of settling
back to sleep, your loyal watchdog comes bounding into your bedroom,
teeth bared, eyes flashing, and starts attacking you. How do you
feel as your flesh is ripped apart? Now you can begin to understand
the shock felt by someone who has been told that their own immune
system-their body's molecular watchdog-has turned traitor. Autoimmune
diseases, including multiple sclerosis, lupus and rheumatoid arthritis,
claim millions of new victims each year. Their methods vary, but
all involve an overzealous immune system attacking the very body
it was designed to defend. Cell by cell, they slowly disable and
ultimately kill many of their victims. Despite decades of research,
few theories have emerged to explain why natural selection would
tolerate such a critical design flaw. Now a few biologists are
starting to point the finger at alien invaders that have been
trapped inside our cells for millions of years. And if they are
right, practices such as gene therapy and xenotransplantation
may be riskier than anyone thought. Researchers agree that the
key to the puzzle of autoimmunity must lie in the major histocompatibility
complex (MHC) -our immune system genes. The MHC is an unusually
diverse region of the genome, which probably reflects our intense
and ongoing co-evolutionary arms race with countless disease organisms.
Each MHC gene in a population can have dozens of versions-or alleles-although
only a couple of these will be present in any given individual.
Over 200 MHC genes are packed tightly together in our genome and
their job is to produce proteins that detect and destroy invaders.
But some MHC alleles or haplotypescombinations of alleles-have
a major drawback: people who carry them are more likely to get
an autoimmune disease. For example, nearly every victim of Hirata's
disease-in which the body attacks its insulin-producing cells-carries
the MHC allele known as DR4wl3. Twothirds of those who suffer
from rheumatoid arthritis possess another risky allele called
DQBI. The haplotypes dubbed DQ and DR also confer an increased
risk of rheumatoid arthritis and type I diabetes. And researchers
have identified dozens more of these associations. But strangely,
not everybody who carries a risky allele or haplotype becomes
ill. So the simplistic notion that these risky alleles lead inexorably
to autoimmune disease has been abandoned in favour of more sophisticated
explanations.

The widely accepted view is that a risky allele must be switched
on before it turns traitor. The trigger is thought to be bits
of foreign proteins, from food or infectious invaders, that resemble
the body's own proteins. MHC alleles that respond to such "molecular
mimics" will then be primed to attack the body's own proteins
as well. Such alleles could persist through evolutionary time
if they help fight off infectious diseases in early life and do
not trigger autoimmune reactions until middle or late life. So
people who carry them are more likely to survive long enough to
reproduce and pass along their double-edged immunological inheritance.
Although this theory doesn't explain susceptibility to diseases
that kick in during childhood, such as type I diabetes, many find
it appealing. Not so Graham Boyd, emeritus professor of medicine
at the University of Tasmania in Hobart. He doesn't attribute
autoimmune diseases to molecular mimics at all. Instead, Boyd
and a growing number of like-minded theorists point to what at
first glance may seem an unlikely culprit: ancient viruses stuck
in the human genome, known as endogenous retroviruses or ERVS.
Outlandish as it sounds, we are the genetic descendants of viruses
as well as primates. The viral ancestors of ERVs invaded the cells
of our forebears during infections millions of years ago and liked
it so much they decided to stay. Happily integrated into their
new home, ERVs have become part of our own genome, passed down
through the generations. In fact, virologists have spotted ERVs
in the genome of every mammal they have checked. Repeated invasions
over more than 30 million years have left a surprisingly large
viral legacy. "Up to 1 per cent of the human genome is represented
by human ERVs and their fragments," says Eugene Sverdlov,
a geneticist at the Russian Academy of Sciences, Moscow.

ERVs are relatively simple creatures, genetically speaking.
Like wild retrovir-uses-which include HIV-they have a few genes
codingfor enzymes and structural proteins. These are sandwiched
between long terminal repeat sequences (LTRs), which act like
on-off switches regulating the production of viral genes. They
are called retroviruses because their genes are encoded in RNA
rather than DNA and they infiltrate the host genome by creating
DNA copies of themselves. Infected cells may then be tricked into
duplicating the viral genes as though they were merely instructions
for one of the body's own cellular proteins (see Diagram, p 40).
Sverdlov calls ERVs "the perpetually mobile footprints of
ancient infections". Many of the resident aliens' genes have
been broken up by mutations, but at least:: a few are still intact
and able to make viral proteins. ERVs also have a nasty habit
of hopping around the genome, duplicating as they go. And either
behaviour- jumping or producing viral proteins could explain why
certain MHC alleles are linked to autoimmune disease. One way
ERVs might trigger autoimmune disease is by causing regulatory
problems in the MHC genes, suggests Klaus Badenhoop from the University
of Frankfurt, Germany. Although nobody knows exactly why, ERVs
appear to have a particular affinity for the MHC region. By some
estimates, they are 10 times as common in the MHC as elsewhere
in our genome. When an ERV's regulatory instructions (its LTR)
land near a host regulatory sequence, the viral on-off switch
can be mistaken for the host's own genetic gadgetry, with disastrous
results. The ERV can enhance or modify the expression of adjacent
genes, says Badenhoop. Together with Ralf Tvnjes from the Paul
Ehrlich Institute in Langen, Germany, and others, Badenhoop is
investigating whether risky MHC alleles might wreak their havoc
because they mistake the ERV instructions for their own, and so
are accidentally switched on. If this is so, you would expect
to find more LTRs near risky alleles than normal MHC alleles.
And this is exactly what Badenhoop and Christian Seidl of the
University of Frankfurt discovered when they looked at the region
around the haplotypes DQ and DR that confer a high risk of type
I diabetes and rheumatoid arthritis. Badenhoop sees promise in
the idea that ERVs contribute to autoimmune disease by causing
confusion within the immune system, but is reluctant to draw firm
conclusions yet. "There is sufficient evidence to regard
ERV long terminal repeats in the MHC as genetic markers for autoimmune
disease," he says. But "their function-how and where
they contribute to pathogenesis-still needs to be elucidated".
Boyd also believes that ERVs could play a role in autoimmune disease.
But instead of seeing people with autoimmune diseases as hapless
victims, he prefers a more co-evolutionary explanation, which
he has dubbed "balanced dynamic polymorphism". Boyd
sees viruses and the hosts they live in as opposing teams in a
dynamic co-evolutionary arms race. Like exotic species settling
in new ecosystems-rats on an island, for example-ERVs can be disruptive
when they first arrive. But like the rats' descendants, the viral
lineages tend eventually to become better adapted to their surroundings.
Once an ERV is integrated into another genome, its survival is
hitched to that of its host. So the longer the association, the
more likely it is that evolution will have quelled an ERV's more
unneighbourly instincts. Boyd likens it to long-running tribal
warfare. "As the years went by," he says, "there
would be a sort of truce whereby the survivors from both sides
would generally agree that all aggression should be curbed."
This truce even goes so far as allowing ERVs to play a major role
in our evolution, by doing away with the need to lay eggs (New
Scientist, 12 June 1999, p 26). And recent studies reveal cases
where viral genes have been co-opted by hosts to serve useful
functions-ironically, often helping to fight disease. One such,
called P-5, is involved in producing immune lymph cells. It has
"a possible role in immunity to retrovirus infection",
says Jerzy Kulski from the University of Westem Australia in Nedlands,
who made the discovery with his colleague Roger Dawkins. Such
domestication events may explain why Badenhoop's team found that
while many risky genes are associated with viral LTRs, at least
one such haplotype lacks them. In this case, the viral on-off
switches are found near normal versions of a gene, suggesting
that they may provide some protection against autoimmune disease.
ERVs can also help defend hosts against wild viruses in other
ways, according to Roswitha Lbwer, a geneticist from the Paul
Ehrlich Institute in Langen, Germany. Chickens and mice are protected
from infection by endogenous proteins that stop viruses sticking
to host cells, Lbwer says. And in mice, ERVs interfere with the
replication of wild viruses inside host cells. Normally, then,
ERVs pose little threat to their hosts. But Boyd believes the
truce is an uneasy one. "There would always be renegade rogues
on both sides," he says. Although most ERVs do not normally
produce the viral proteins that provoke attack from the host immune
system, many retain the genetic code for such particles. This
unwillingness to disarm, Boyd believes, may set the stage for
autoimmune disease. ERVs that retain their protein-producing potential
are more like tenuously tamed wolves than loyal puppy dogs. Every
once in a while these ERVs awake from their civilised slumber
and begin pumping out viral proteins. So what makes domesticated
ERVs turn feral? Lower speculates that UV light and bacteria are
possible alarm clocks that wake ERVS. Boyd believes that the key
is repeated damage to cells, either from infection by wild viruses
or from severe psychological stress. The effects of such stress
can affect the sympathetic nerves controlling arterial blood supply.
If the nerves are shut down, the temporary loss of blood supply
can cause cellular damage, which might contribute to ERV activation,
according to Boyd. Either way, once ERVs start producing molecules
that look like antigens from wild viruses, MHC genes may kick
in to fight off the perceived invasion. The result is an immune
attack against your own cells. The question then is why natural
selection hasn't eliminated those MHC alleles prone to mistake
ERV products for infections. Boyd argues that hosts are in an
evolutionary bind, a Darwinian catch-22. So long as wild relatives
of ERVs exist in nature and pose a threat, there will be a survival
advantage in possessing MHC alleles that can fight them off-even
though individuals carrying such alleles are susceptible to autoimmune
disease. His ideas fit in with today's knowledge of autoimmune
susceptibility alleles and ERVs. He believes that the conflicting
selection pressures for maintaining and eliminating risky MHC
alleles-those that mistake ERV proteins for foreign invaders-result
in some, but not all, individuals possessing dangerous alleles.
If he is right, geneticists will find geographic pattems in the
distribution of risky alleles that reflect varying disease risks.
For the moment, the jury is still out on whether ERVs are an accessory
to autoimmune disease. if they are, the implications for medicine
are wide-ranging. Lower is particularly concemed about gene therapy
and cross-species organ transplantation. The retroviruses used
as vehicles in gene therapy might activate a patient's ERVSAnd
the promise of plentiful supplies of organs from pigs and baboons
for use in xenotransplantation may be dangerous for similar reasons.
The ERVs in pigs and primates, Lbwer points out, are close relatives
of ours. "There is a risk of uncontrolled human ERV amplifications,"
she says. Lbwer's concems seem well founded. Earlier this year,
a team of her colleagues led by Frank Czauderna reported that
some pig ERVs do indeed code for viable viruses. Worse still,
the(se viruses can replicate in human tissues, at least under
lab conditions. Czauderna worries that pig and human ERVs could
hybridise, yielding infectious viruses with new and unfamiliar
properties. But he is hopeful that it will be possible to use
genetic engineering techniques to knock out pig ERVs and create
a cloned lineage of donor animals for xenotransplantations. And
there is a more positive side to all this: it could lead to ways
of fighting off diseases that now seem to strike at random. If
ERVs are activated by repeated stress, as Boyd suspects, then
identifying and avoiding such stress could one day eliminate the
immunological betrayals that lead to disease. "Autoimmune
dis ease is not inevitable," says Boyd.1-1